Naltrexone is chemically 17-(cyclopropylmethyl)-4,5-epoxy-3, 14 dihydroxy-(5alpha)-morphinan-6-one, CAS RN 16590-41-3. Common trade names include Trexan® and Revia®. Naltrexone is an opioid antagonist with no agonist properties. It markedly blocks the physical dependence to opioids. Naltrexone is also used in reducing the craving for alcohol in treating alcoholism.
Methods for the synthesis of naltrexone have been described and are well known in the art. The overall molar yield of the conventional process from noroxymorphone to naltrexone hydrochloride has been reported to be about 65%. The overall yield to the anhydrous naltrexone base is typically about 45%. The levels of typical impurities, such as N-(3-butenyl)noroxymorphone (3BN) and 2,2-bisnaltrexone (2BN), need to be reduced to less than 0.50 area % to meet federal purity standards. There is therefore a need for a more efficient and direct method to isolate highly pure naltrexone, especially when producing industrial quantities.
Means to achieve separation or purification of pharmaceuticals include adsorption processes such as the use of carbon. Unfortunately, the carbon irreversibly adsorbs the pharmaceutical of interest in addition to removing color and other unwanted substances. This results in a significant yield loss.
In some instances, as in naltrexone, multiple precipitations are required in order to achieve the desired purity. This greatly reduces the overall yield when the supernatant streams are not recycled. These additional precipitations also require using a greater volume of naltrexone in the process with longer cycle times. Furthermore, the precipitation process can be lengthy in addition to the time that is sometimes required for heating and cooling. Moreover, some precipitations require extended filtration time due to the particle size of the product that is eventually produced.
Other drawbacks to the conventional process of purifying naltrexone include multiple manual solid handling operations to recover the naltrexone. These operations lead to greater operator exposure to the naltrexone with the associated reliance on engineering controls and personal protective equipment. This operation can be monotonous as well as tedious.
Another approach to purify naltrexone is the use of adsorption through ion exchange. Although this has been accomplished with alkaloids such as codeine and morphine, it has the limitation of requiring a low feed concentration. This is due to the need for the use of high pH flushes that can cause precipitation. Any precipitation can potentially compromise the entire ion-exchange resin column. Another disadvantage to this process is that due to the significant salt requirements, an additional step of dialysis or reverse osmosis is required for ion-removal.
Yet another process to achieve adsorption is through polar interaction or normal phase adsorption. Although this method can be successful, it requires extensive use of organic solvents. Moreover, although the naltrexone could be purified in this manner, more evaporation would be required.
Any use of analytical chromatography on naltrexone would guide an individual of ordinary skill in the art away from using preparative chromatography for an industrial scale process. Unlike preparative chromatography, analytical chromatography generally requires complete separation of each peak. The elution of the component peaks is measured often through the absorbance of ultraviolet (UV) light. In analytical chromatography the peak separation is achieved by loading an infinitely small mass of the feed onto the column, and using a small particle size diameter (often less than 5 micrometers in the stationary phase.) The small particle size generates much higher pressures than those found in preparative chromatography. These higher pressures mandate the use of very large, strong and expensive chromatography equipment, which would negate the commercial viability for this analytical process. The equipment would also be very large in consideration that an infinitely small mass of feed is loaded in each run. In preparative chromatography, the objective is to recover the desired feed component with the required purity. The desired component can be recovered with impurities, so long as the impurities are within specification limits. The particle size of the stationary phase is small enough to achieve the separation, but is often greater than 10 microns. This limits the pressure drop generated. Also, in preparative chromatography, the maximum amount of feed is loaded with the constraint of attaining the desired product quality. This allows the product to leave the column with a maximum concentration, which thereby minimizes the size of the downstream equipment, especially the evaporating or concentrating units.
The separation or purification of organics by means of chromatographic processes is well known in the art. However, the materials separated by means of the chromatographic processes are greatly dissimilar to the present objects of this invention, i.e. the industrial scale separation and purification of naltrexone. While there are numerous references to analytical chromatographic applications for naltrexone, there is no suggestion that an industrial process could be employed under previously known conditions.
The present invention is directed to overcoming one or more of the deficiencies set forth above. These deficiencies include, but are not limited to, product yield loss, tedious manual solid handling operations such as the loading and unloading of centrifuges or filters, reliance on protective equipment by the operator, extensive processing steps and multiple precipitations in order to achieve the requisite purity requirements.